tbuckley/cabot-search huggingface dataset:
Abstract 4632: Spatial whole transcriptome analysis of differential expression for biomarker discovery in colorectal cancer
Authors: Elim Cheung, Vidyodhaya Sundaram, Baowen Zhang, Lutong Zhang, Tong Lu
Journal: Cancer Research (2023)

Abstract Background: Colorectal cancer (CRC) is one of the leading causes of cancer death, which is frequently caused by genetic or epigenetic changes. The study of tumor microenvironment (TME) profiling may provide a better knowledge of spatial gene expression patterns of known CRC markers, visualize the cell composition and localization, and serve to aid the understanding of the mechanisms of tumor formation. BioChain Institute, Inc. is currently investigating the TME profiling of CRC through tissue-wide, whole transcriptome analysis for the ability to discover potential therapeutic targets. Methods: BioChain’s formalin-fixed paraffin-embedded (FFPE) tissue samples from 3 primary colon adenocarcinoma tumors (PT), and their matched adjacent normal tissues (PN), were used to investigate the TME. The images of Hematoxylin and Eosin (H&amp;E)-stained tissue sections were annotated by our pathologist. The spatial whole transcriptome was analyzed using 10x Genomics Visium Spatial Gene Expression for FFPE. This assay provided about 5,000 spatially barcoded spots with mRNA-binding oligonucleotides to capture the gene expression. The integration of the imaging and sequencing data enabled a spatially resolved transcriptome of CRC heterogeneity. Results: The annotations of both PT and PN tissue samples were found to be correlated with the spatial gene expression clustering. With the overlaying of total gene counts for each spot on the H&amp;E-stained tissue image, about 16,000-17,000 genes were detected in each sample. The median of ~5,500 and ~1,600 genes per spot were expressed in PT and PN samples respectively. The study of gene expression levels revealed the overexpression of several well-known CRC markers (APOE, SCD, IGFBP3, TIMP1, SPARC) and the down-regulation of numerous markers (DES, CA1, KLF4) in PT samples significantly. Conclusion: Our spatial analysis results provide insight into tumor heterogeneity, spatial organization of cells within the TME and biomarker identification. BioChain is in a unique position to facilitate researchers with a plethora of oncologic and other diseased tissue types, as well as the spatial whole transcriptome analysis. Our study enables the understanding of the TME, discovery of potential diagnostic and prognostic targets, especially for the development of personalized therapy. Citation Format: Elim Cheung, Vidyodhaya Sundaram, Baowen Zhang, Lutong Zhang, Tong Lu. Spatial whole transcriptome analysis of differential expression for biomarker discovery in colorectal cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4632.
Abstract 3485: Intrinsically disordered regions of the ARID1A/B tumor suppressors encode an interaction network within biomolecular condensates that directs mSWI/SNF chromatin remodeler complex activity
Authors: Ajinkya Patil, Amy R. Strom, Clayton K. Collings, Joao A. Paulo, Tobias Wauer, Akshay Sankar, Jessica D. St.Laurent, Kasey S. Cervantes, Steven P. Gygi, Clifford P. Brangwynne, Cigall Kadoch
Journal: Cancer Research (2023)

Abstract The mammalian SWI/SNF (mSWI/SNF or BAF) ATP-dependent chromatin remodeling complexes collectively represent one of the most frequently mutated cellular entities in cancer, second only to TP53. Mutations across the 29 human genes that encode mSWI/SNF complex subunits occur in over 20% of human cancers, with mutations affecting ARID1A and ARID1B, the largest BAF subunits, being the most frequent. However, the functional contributions of these subunits, particularly their commonly mutated N-terminal intrinsically disordered regions (IDRs) and a highly conserved ARID DNA-binding domain, to BAF function remain poorly understood. Here, we demonstrate that the IDRs of ARID1A/B, coupled with the ARID domain, drive biomolecular condensate formation and BAF chromatin localization in cells. We define ARID1A/B IDRs as two-part systems, facilitating homotypic BAF complex interactions (i.e., valence generated by localized condensation) and heterotypic complex interactions, that together establish a highly specific, sequence-encoded protein interaction network within condensates. Both types of interactions are required for appropriate genome-wide targeting of BAF complexes, DNA accessibility generation, and appropriate gene expression. Replacement of the ARID1A N-terminal IDR with IDRs derived from two unrelated proteins FUS and DDX4, rescues generic condensation of BAF but not chromatin occupancy, DNA accessibility, and heterotypic interactions, highlighting the sequence-specificity embedded in the IDR of ARID1A. Taken together, these data establish a role for the largest and most frequently perturbed IDRs within a major chromatin remodeler and explain how biomolecular condensate formation enables both genomic localization and functional partner recruitment. Furthermore, these findings lay the groundwork for mapping IDR sequence specificity or “grammar”, that dictates the co-condensation network formation, and suggests that targeted disruption of these mechanisms may represent new targeted therapeutic opportunities across multiple cancers. Citation Format: Ajinkya Patil, Amy R. Strom, Clayton K. Collings, Joao A. Paulo, Tobias Wauer, Akshay Sankar, Jessica D. St.Laurent, Kasey S. Cervantes, Steven P. Gygi, Clifford P. Brangwynne, Cigall Kadoch. Intrinsically disordered regions of the ARID1A/B tumor suppressors encode an interaction network within biomolecular condensates that directs mSWI/SNF chromatin remodeler complex activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3485.
Abstract 3237: Dovitinib restricts EMT and promotes T cell recruitment to immune-desert gastric cancers via tumor-intrinsic IFN-γ signaling
Authors: Heng Lu, Longlong Cao, Mohammed Soutto, Nadeem Bhat, Zheng Chen, Dunfa Peng, Ahmed Gomaa, Sachiyo Nomura, Jashodeep Datta, Alexander Zaika, Wael El-Rifai
Journal: Cancer Research (2023)

Abstract Background: Gastric cancer (GC) ranks fifth in incidence and fourth for mortality worldwide. The response to immune checkpoint blockade (ICB) therapy in GC is heterogeneous due to tumor-intrinsic and acquired immunotherapy resistance. Methods: A novel immunophenotype-based subtyping algorithm was established to analyze tumor patient-derived bulk transcriptomic data. Gene set enrichment assays (GSEA), in vitro cell models, multiple syngeneic murine tumor models, and immune-checkpoint blockade (ICB) therapy were utilized. Results: Our algorithm stratified human GC and showed that immune desert- and excluded-type tumors are ICB-resistant compared with immune-inflamed GC. Moreover, epithelial-mesenchymal transition (EMT) signaling is highly enriched in immune desert-type GC, and syngeneic murine tumors exhibiting mesenchymal-like, compared with epithelial-like, properties are T cell-excluded and resistant to CTLA4 blockade. Our analysis further identifies a panel of receptor tyrosine kinases (RTKs) as potential druggable targets in the immune desert-type GC. Dovitinib, an inhibitor of multiple RTKs, strikingly repressed EMT programming in mesenchymal-like immune desert syngeneic GC models. Dovitinib activates the tumor-intrinsic SNAI1/2-IFN-γ signaling axis and impedes the EMT program converting immune desert-type tumors to immune inflamed-type tumors, sensitizing these mesenchymal-like ‘cold’ tumors to CTLA4 blockade. Conclusion: We develop a novel immunophenotype-based algorithm to reclassify GC into immune inflamed, excluded, and desert subtypes. Our analysis identified major signaling pathways and potential druggable targets relevant to patient groups, especially for refractory immune desert-type/‘cold’ tumors. Dovitinib, an RTK inhibitor, sensitizes desert-type immune-cold GCs to CTLA4 blockade and possibly in a broad spectrum of other solid tumors. Citation Format: Heng Lu, Longlong Cao, Mohammed Soutto, Nadeem Bhat, Zheng Chen, Dunfa Peng, Ahmed Gomaa, Sachiyo Nomura, Jashodeep Datta, Alexander Zaika, Wael El-Rifai. Dovitinib restricts EMT and promotes T cell recruitment to immune-desert gastric cancers via tumor-intrinsic IFN-γ signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3237.
Abstract 1074: The potential of 18β-glycyrrhetinic acid benefit lenvatinib induced cytotoxicity on hepatocellular carcinoma
Authors: Yeh Pei-Wen, Yu-Chiang Liu, Yuan Chang, Jiann-Hwa Chen
Journal: Cancer Research (2023)

Abstract Hepatocellular carcinoma (HCC) is usually caused by long-term inflammation such as infected by hepatitis B and C viruses. The current standard treatment methods of HCC has included with general surgery, radiation, etc. However, the recurrence rate remain high even after standard treatment, it is necessary to find a better treatment option to control the progression of HCC. Lenvatinib is a multi-endothelial angiogenesis factor inhibitor which is a first-line target drug for the treatment of advanced HCC. Some studies indicated that activation of the PI3K/AKT pathway could lead to the resistance effect of lenvatinib in HCC. 18β-glycyrrhetinic acid (18β-GA) is a hydrolyzed product of glycyrrhizic acid in the intestine. Studies reported that 18β-GA can effectively treat inflammatory diseases and may have antitumor potential. Some studies also indicated that 18β-GA can down-regulate the signaling transduction of PI3K/AKT pathway in various type of cancers. Therefore, in this study, we focused on exploring whether 18β-GA can be used as an adjuvant to downregulate PI3K/AKT signaling and thus enhance the efficacy of lenvatinib on HCC cells and animal model. Here, we used the MTT assay to investigate the cytotoxicity of HCC cells (Huh7 and Hep3B) after various dose of lenvatinib and (or) 18β-GA treatment. We also used combination index (CI) to evaluate the suitable combination condition. In our results, the CI value of lenvatinib 30 μM combined with 18β-GA 100 μM is smaller than 1, which indicated the synergistic effect of combination. We confirmed the superior extrinsic/intrinsic apoptosis induction ability was found in lenvatinib combined with 18β-GA as compared to single treatment. The activation of Fas/FasL pathway, Annexin V, cleaved caspase-3, -8 and -9 were used to confirm the apoptosis induction by lenvatinib combined with 18β-GA. Transwell invasion and wound healing assays results also indicated the invasion/migration suppression ability of lenvatinib combined with 18β-GA on HCC cells. The phosphorylation of AKT were markedly decreased by lenvatinib combined with 18β-GA in HCC cells. Hep3B bearing animal data proved the superior tumor control of lenvatinib combined with 18β-GA. Additionally, the liver function and normal tissue pathology may not affect by combination of lenvatinib and 18β-GA. To conclude, our result demonstrated that 18β-GA may sensitize HCC to lenvatinib via inactivation of PI3K/AKT signaling pathway and induction of extrinsic/intrinsic apoptosis signaling. Citation Format: Yeh Pei-Wen, Yu-Chiang Liu, Yuan Chang, Jiann-Hwa Chen. The potential of 18β-glycyrrhetinic acid benefit lenvatinib induced cytotoxicity on hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1074.
Abstract 317: Particulate matter accumulates chromosomal instability during mitosis
Authors: Jaewook Ryu, Ja-Eun Kim
Journal: Cancer Research (2023)

Abstract Particulate matter (PM), a major component of outdoor air pollution triggers genotoxicity as well as cytotoxicity. Although the harmful effects of PM on DNA damage and its carcinogenic risk have been thoroughly studied, the detailed mechanism by which PM affects chromosomal stability remains unclear. Maintenance of chromosome is finely monitored during mitotic phase through multiple proteins and structures. The present study shows that treatment of urban particulate matter (UPM) inhibited proliferation of lung cells through the accumulation of chromosomal instability which is determined by the formation of multinucleation and macronucleation. In particular, PM treatment prolonged mitotic duration. This delay in mitotic progression resulted from inactivation of Aurora B at prometaphase and metaphase, causing a failure in dynamic stabilization of kinetochore-microtubule attachment. In addition, ingression rate of cleavage furrow and actin clearing from polar cortex were significantly reduced at telophase. It indicates that dysregulation of spatiotemporal dynamics of mitotic proteins and structures finally disturbs cytokinetic division. Overall, PM leads to accumulation of chromosomal instability, finally contributing to its carcinogenicity. Citation Format: Jaewook Ryu, Ja-Eun Kim. Particulate matter accumulates chromosomal instability during mitosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 317.
Abstract 4353: Utilizing scRNA sequencing to understand biomarkers of response and resistance to Sacitizumab Govetican in localized TNBC
Authors: Nicole Peiris, Simona Cristea, Mengran Zhang, Siang Koh, James Coates, Ilze Smidt, Veerle Bossuyt, Laura Spring, Aditya Bardia, Leif Ellisen
Journal: Cancer Research (2023)

Abstract Triple-Negative Breast Cancer (TNBC) is an aggressive breast cancer subset, which lacks expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor-2. This subset of breast cancer disproportionately affects Black and African American women and improving TNBC treatment options is vital to reducing breast cancer mortality. The novel antibody-drug conjugate, Sacitizumab Govetican (SG), which targets TROP2 at the cell surface, has shown promising clinical results from the NeoSTAR trial (NCT04230109), a phase II study evaluating neoadjuvant SG therapy in a localized TNBC setting. As part of the NeoSTAR clinical trial, we have collected and processed pre- and post- SG treatment patient samples, with the aim of understanding response to this monotherapy. Herein, we identify biomarkers of response and resistance to SG monotherapy through the use of single cell RNA sequencing of matched pre- and post-treatment patient biopsies combined with exome sequencing these patient samples. Pre-treatment core needle biopsy samples, and if applicable, post-treatment residual disease biopsies were dissociated into single cell suspensions and subjected to single cell RNA sequencing. Additionally, fixed patient tissue samples were processed accordingly for exome sequencing analyses. Overall, we analyzed over 144,000 cells from 37 total scRNA seq libraries with an average of 3800 cells per biopsy sample, demonstrating the feasibility of this method. From these analyses, we observed several cell-type differences between patients who achieved a pathological complete response (pCR) and patients who had residual disease (RD). Specifically, our data shows that tumor infiltrating lymphocytes are a potential prognostic biomarker of response to SG. Furthermore, we detected alterations in among stromal and immune cell subsets, among non-responders, indicating that these cell types maybe indicative of SG resistance. Taken together, we outline biomarkers of response to SG treatment for an improved understanding of resistance mechanisms in the neoadjuvant setting to improve TNBC outcomes among patients. Citation Format: Nicole Peiris, Simona Cristea, Mengran Zhang, Siang Koh, James Coates, Ilze Smidt, Veerle Bossuyt, Laura Spring, Aditya Bardia, Leif Ellisen. Utilizing scRNA sequencing to understand biomarkers of response and resistance to Sacitizumab Govetican in localized TNBC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4353.
Abstract 3293: CADM1 is a serum marker for small-cell lung cancer associated with poor prognosis and metastasis
Authors: Takeshi Ito, Toko Funaki, Hiroko Iwanari, Goh Tanaka, Takahide Nagase, Takao Hamakubo, Yoshinori Murakami
Journal: Cancer Research (2023)

Abstract Small-cell lung cancer (SCLC) is aggressive neuroendocrine cancer that accounts for approximately 15% of lung cancer. Although chemotherapy is effective for SCLC, resistant tumors develop rapidly; therefore, early detection in the initial screening and after chemotherapy is one of the critical issues in controlling SCLC progression. For this purpose, neuron-specific enolase (NSE) and pro-gastrin-releasing peptide (ProGRP) are used as tumor markers for SCLC but are not sensitive enough, especially in the early stages. Previously we found that Cell adhesion molecule 1 (CADM1) is highly expressed in SCLC, and an SCLC-specific splicing variant, CADM1v8/9, is selectively cleaved by ADAM17 protease to release the extracellular fragments. Here, we report that soluble CADM1v8/9 fragments (sCADM1v8/9) can be a serum marker of SCLC associated with poor prognosis and metastasis. Immunohistochemical analysis showed that the expression of CADM1 was observed in 83% of the resected SCLC cases and strongly correlated with that of INSM1, a marker of neuroendocrine differentiation. The high expression of CADM1 was associated with poor prognosis and nodal involvement, which was supported by experimental data showing that CADM1 promoted subcutaneous tumor growth and lymph node metastasis of SCLC cells in nude mice. Moreover, sCADM1v8/9 distinguished 47% of SCLC, including a significant portion of patients with limited disease SCLC, independent of and partly overlapped with the cases detected by ProGRP or NSE. Notably, a high amount of sCADM1v8/9 was observed in SCLC cases with liver metastasis or pleural effusion. Furthermore, serum levels of sCADM1v8/9 well reflected the change in tumor burden before and after chemotherapy. These findings indicate that detecting sCADM1v8/9 in sera would provide clinical benefits in diagnosis, follow-up, and metastasis prediction of SCLC cases. Citation Format: Takeshi Ito, Toko Funaki, Hiroko Iwanari, Goh Tanaka, Takahide Nagase, Takao Hamakubo, Yoshinori Murakami. CADM1 is a serum marker for small-cell lung cancer associated with poor prognosis and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3293.
Abstract 2941: ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent <i>in vitro</i> and <i>vivo</i> antitumor activity and superior safety profile
Authors: Yangsoon Lee, Kyeong-Su Park, Wonjun Son, Sora Kim, Hyunseong Youn, Jiseon Yoo, Hanbyul Lee, Jonghwa Won
Journal: Cancer Research (2023)

Abstract ROR1, a member of the ROR (Receptor Tyrosine Kinase-Like Orphan Receptor)-family, is overexpressed in the process of embryo and fetal development, and controls cell polarity, cell migration and neurite growth. The expression is gradually reduced as development progresses, and it is hardly expressed in adults, but the overexpression of ROR1 is observed in various blood and solid cancer cells, so it is classified as an oncofetal gene. ABL102, a First-in-Class bispecific antibody targeting ROR1 and 4-1BB, elicits superior T cell activation by tumor specific T cell engagement through ROR1 dependent 4-1BB clustering. Our data showed that tumor target dependents binding of ROR1 and costimulatory 4-1BB by ABL102 induced 4-1BB activation in cell-based 4-1BB bioassay. ABL102 lead to IFN-γ secretion and tumor cell killing with a ROR1 dependent manner in co-culture assay with tumor cells and human PBMC. In h4-1BB knock-in mouse model bearing hROR1-expressing tumors, ABL102 potently inhibited tumor progression with a high rate of complete remission (CR). Mice with CR were further protected from the rechallenge of previously exposed tumors after 3 months of cessation of ABL102 treatment, implicating that immunological memory might be generated. In 4-week pilot toxicity study using cynomolgus monkeys, no ABL102-related toxicity was observed up to 100mg/kg, including mortality, body weight, hematology, liver toxicity, clinical chemistry and pathology, indicating a favorable safety profile. In conclusion, ABL102 exhibited potent in vitro and vivo anti-tumor activity and it was well tolerated and safe in the NHP toxicity study. These results strongly suggest that ABL102 is promising therapeutics for ROR1 positive cancer patients. Citation Format: Yangsoon Lee, Kyeong-Su Park, Wonjun Son, Sora Kim, Hyunseong Youn, Jiseon Yoo, Hanbyul Lee, Jonghwa Won. ROR1 targeted 4-1BB costimulatory bispecific antibody, ABL102, exhibits potent in vitro and vivo antitumor activity and superior safety profile [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2941.